Thyroid cancer is now increasing in incidence in the United States more rapidly than any other cancer in both men and women (Edwards et al. 2005 J Natl Cancer Inst 97:1407-1427). The American Cancer Society estimates that, in the United States, 25,690 people (6,500 men and 19,190 women) were diagnosed with and 1,490 people died of cancer of the thyroid in 2005 with prevalence exceeding 327,000 in 2002. Global data from 2002 show an incidence of 141,000 new cases (Parkin et al. 2002. CA Cancer J Clin 55:74-108). Age-specific incidence rates reveal thyroid cancer to have a higher incidence than all other cancers in white women between the ages of 20 to 30 (Wu et al. 2005 Cancer Causes Control 16:309-320). The most current SEER Data (National Cancer Institute, Bethesda, Md.; posted 2006) evaluating trends in cancer incidence and death from 1994 to 2003 documents thyroid carcinoma exceeding all other cancers in rate of increased incidence and second only to liver/intrahepatic bile duct cancers in rate of increased death. This most rapid rate of incidence increase for thyroid cancer is seen both in people over 65 yrs and under 65 yrs of age and in both men and women.
Radioiodide is a “magic bullet” for systemic therapy of thyroid carcinoma. Radioiodine treatment is an effective post-surgical therapy with unique specificity for differentiated thyroid carcinoma cells that retain the ability to concentrate iodine (DeGroot et al. 1994 Wold J Surg 18:123-130; Mazzaferri et al. 1994 Am J Med 97:418-428; Samaan et al. 1992 J Clin Endocrinol Metab 75:714-720; Simpson et al. 1988 Int J Rad One Biol Phys 14:1063-1075; Wong et al. 1990 Endocrinol Metab Clin N Amer 19:741-760). Successful destruction of malignant thyroid cells requires delivery of a sufficient total radiation dosage using I131 while at a dose rate of 0.6 to 3.0 Gy/h in order to prevent cellular repair of sublethal radiation damage. The efficacy of this treatment requires thyroid cancer cells to manifest “differentiated” functional abilities. Differentiated functions include: expression and membrane-localization of the sodium/iodide symporter (NIS) enabling intracellular concentration of radioiodide, expression of thyrotropin (TSH) receptors (permitting both stimulation of the cell and increased hNIS production by raising TSH levels and suppression of the cell by decreasing TSH levels), organification of internalized iodide (enhancing radioiodide retention and radiation dose delivery), and production of thyroglobulin (clinically useful as a specific tumor marker in thyroidectomized patients).
NIS actively transports iodide into thyroid follicular cells against an electrochemical gradient, by a factor of 20-40, for organification by thyroid peroxidase in the cell. This process is stimulated by thyrotropin (TSH) and powered by Na+/K+-ATPase. Normal thyroid, stimulated by TSH, concentrates I131 (uptake) to 1% of administered dose/gram tissue. Differentiated thyroid cancer metastases typically concentrate I131 at 0.06 to 0.3% of administered I131 dose/gram tumor (3-17-fold less than normal thyroid tissue).
Undifferentiated and dedifferentiated thyroid carcinoma, however, constitute a broad spectrum of tumors that show varying degrees of differentiated function and clinical aggressiveness. This is epitomized by anaplastic carcinomas with median survival measured in months despite the most assertive therapeutic efforts (Ain K B 1999 Seminars in surgical oncology 16:64-69; Ain K B 1998 Thyroid 8:715-726). Despite the fact that fewer than 400 new cases of anaplastic thyroid carcinoma are expected in North America each year, thousands of patients will manifest poorly differentiated metastatic thyroid cancers with sufficient loss of differentiated function to make classical treatment with radioactive iodine ineffectual, constituting at least one third of patients with distant metastases (Schlumberger et al. 1996 J Nucl Med 37:598-605). In most cases, the failure of radioiodine treatment is due to loss of NIS function, which ultimately result in ≈10% of patients die (Robbins et al. 1991 Ann Int Med 115:133-147).
Therefore, there exists a need for restoring the expression or function of NIS in thyroid cancer cells to facilitate the uptake and/or retention of radioactive iodine in such cells in which NIS expression and/or function is reduced or lost.